Failed stem cells may cause deadly lung disease

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Breathing is something we take for granted. It’s automatic. We don’t need to think about it. But for people with pulmonary fibrosis, breathing is something that is always on their minds.

Pulmonary fibrosis (PF) is a disease where the tissue in your lungs becomes thick and stiff, even scarred, making it difficult to breathe. It can be a frightening experience; and it doesn’t just affect your lungs.

Because your lungs don’t work properly they aren’t able to move as much oxygen as you need into your bloodstream, and that can have an impact on all your other organs, such as your brain and heart. There are some treatments but no cures, in large part because we didn’t know the cause of the disease. Many patients with PF live only 3-5 years after diagnosis.

Now a new CIRM-funded study from researchers at Cedars-Sinai has uncovered clues as to the cause of the disease, and that in turn could pave the way to new treatments.

The study, published in the journal Nature, found that a class of stem cells in the lung, called AEC2s, are responsible for helping repair damage caused by things such as pollution or infection. People who have PF have far fewer of these AEC2 cells, and those cells also had a much lower concentration of a chemical substance called hyaluronan, which is essential for repair damaged tissue.

They tested this theory with laboratory mice and found that by removing hyaluronan the mice developed thick scarring in their lungs.

In a news release from Cedars-Sinai Carol Liang, the study’s first author, said knowing the cause of the problem may help identify potential solutions:

“These findings are the first published evidence that idiopathic pulmonary fibrosis is primarily a disease of AEC2 stem cell failure. In further studies, we will explore how the loss of hyaluronan promotes fibrosis and how it might be restored to cell surfaces. These endeavors could lead to new therapeutic approaches.”

Knowing that a problem with AEC2 cells causes PF means the researchers can now start testing different medications to see which ones might help boost production of replacement AEC2 cells, or help protect those still functioning.

Seeing is Believing: New Video on the Power of Stem Cells

skepticThe world is full of skeptics. Remember when you first heard about self-driving cars? I’m sure that information was met with comments like, “When pigs fly!” or “I’ll believe it when I see it!” Well, it turns out that the best way to get people to believe something is possible, is to show them.

And that’s our mission at CIRM. To show people that stem cell research is important and funding it is essential for the development of future therapies that can help patients with all sorts of diseases be they rare, acute, or chronic.

We’re doing this in multiple ways through our Stem Cellar blog and social media channels where we post about the latest advances in regenerative medicine research towards the clinic, through disease walks and support groups where we educate patients about stem cells, and through fun and engaging videos about the cutting-edge research that our agency is funding.

Last month, the world celebrated Stem Cell Awareness Day on October 12th. One of the ways we celebrated at CIRM was to give talks at local institutes about the power of stem cells for research and therapeutic development. One of these talks was at the Buck Institute for Research on Aging in Novato as part of their special public event on “Turning Promise of Regenerative Medicine into Reality” supported by the STEAM ENGINE, the teacher outreach program at the Buck Institute.

Kevin, CIRM’s communicators director, and I did a joint presentation on the different ways that scientists are using stem cells to model disease and to develop new treatments for patients. We also shared a few particularly exciting stories about new stem cell advancements that are being tested in clinical trials. One of them was a heartbreaking turned heartwarming story of Evangelina, a baby born with severe combined immunodeficiency (SCID), a disease that leaves children without a functioning immune system and often kills babies within a year of birth. Evangelina was part of a CIRM-funded clinical trial run by UC Los Angeles that transplanted the patient’s own genetically corrected blood stem cells. Evangelina is one of 30 children the UCLA team has cured and CIRM is now funding a Phase 2 clinical trial for this work.

Our talk was followed by exciting stories of stem cell research in the lab. Three talented postdoctoral fellows, who spoke about new developments in stem cell therapies for HIV, degenerative eye disease and neurodegenerative diseases. The talks were well received by the audience, who were actively speaking up to ask questions during the panel discussion with the speakers.

Panel on stem cells.

Stem cell panel: Kevin McCormack, Imilce Rodriguez-Fernandez, Joana Neves, Karen Ring.

It was a truly inspiring day full of learning and excitement about the future of stem cell research and regenerative medicine. But for the skeptics out there, don’t take my word for it, you can see for yourself by can watching the video recording here:


Related Links:

First spinal cord injury trial patient gets maximum stem cell dose

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Kris Boesen, CIRM spinal cord injury clinical trial patient.

There comes a pivotal point in every experiment where you say “ok, now we are going to see if this really works.” We may be at that point in the clinical trial we are funding to see if stem cells can help people with spinal cord injuries.

Today Asterias Biotherapeutics announced they have given the first patient in the clinical trial the highest dose of 20 million cells. The therapy was administered at Santa Clara Valley Medical Center (SCVMC) in San Jose, California where Jake Javier – a young man who was treated at an earlier stage of the trial – was treated. You can read Jake’s story here.

The goal of the trial is to test the safety of transplanting three escalating doses of AST-OPC1 cells. These are a form of cell called oligodendrocyte progenitors, which are capable of becoming several different kinds of nerve cells, some of which play a supporting role and help protect nerve cells in the central nervous system – the area damaged in spinal cord injury.

In a news release, Dr. Edward Wirth, Asterias’ Chief Medical Officer, says this could be a crucial phase in the trial:

“We have been very encouraged by the early clinical efficacy and safety data for AST-OPC1, and we now look forward to evaluating the 20 million cell dose in complete cervical spinal cord injury patients. Based on extensive pre-clinical research, this is in the dosing range where we would expect to see optimal clinical improvement in these patients.”

To be eligible, individuals have to have experienced a severe neck injury in the last 30 days, one that has left them with no sensation or movement below the level of their injury, and that means they have typically lost all lower limb function and most hand and arm function.

In the first phase individuals were given 2 million cells. This was primarily to make sure that this approach was safe and wouldn’t cause any problems for the patients. The second phase boosted that dose to ten million cells. That was thought to be about half the therapeutic dose but it seemed to help all those enrolled. By 90 days after the transplant all five patients treated with ten million cells had shown some level of recovery of at least one motor level, meaning they had regained some use of their arms and/or hands on at least one side of their body. Two of the patients experienced an improvement of two motor levels. Perhaps the most impressive was Kris Boesen, who regained movement and strength in both his arms and hands. He says he is even experiencing some movement in his legs.

All this is, of course, tremendously encouraging, but we also have to sound a note of caution. Sometimes individuals experience spontaneous recovery after an accident like this. The fact that all five patients in the 10 million cell group did well suggests that this may be more than just a coincidence. That’s why this next group, the 20 million cell cohort, is so important.

As Steve McKenna, Chief of the Trauma Center at SCVMC, says; if we are truly going to see an improvement in people’s condition because of the stem cell transplant, this is when we would expect to see it:

“The early efficacy results presented in September from the 10 million cell AIS-A cohort were quite encouraging, and we’re looking forward to seeing if those meaningful functional improvements are maintained through six months and beyond. We are also looking forward to seeing the results in patients from the higher 20 million cell AST-OPC1 dose, as well as results in the first AIS-B patients.”

For more information about the Asterias clinical trial, including locations and eligibility requirements, go here: www.clinicaltrials.gov, using Identifier NCT02302157, and at the SCiStar Study Website (www.SCiStar-study.com).

We can never talk about this clinical trial without paying tribute to a tremendous patient advocate and a great champion of stem cell research, Roman Reed. He’s the driving force behind the Roman Reed Spinal Cord Injury Research Act  which helped fund the pioneering research of Dr. Hans Keirstead that laid the groundwork for this clinical trial.

 

 

Discovering stem cells and science at Discovery Day

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The CIRM booth at Discovery Day at AT&T Park

Someone stole my thigh bone. One minute it was there. The next, gone. I have narrowed down the list of suspects to the more than 25,000 people attending Discovery Day at San Francisco’s AT&T Park.

To be honest, the bone was just a laminated image of a bone, stuck to the image of a person drawn on a white board. We were using it, along with laminated images of a brain, liver, stomach and other organs and tissues, to show that there are many different kinds of stem cells in the body, and they all have different potential uses.

The white board and its body parts were gimmicks that we used to get kids to come up to the CIRM booth and ask what we were doing. Then, as they played with the images, and tried to guess which stem cells went where, we talked to their parents about stem cell research, and CIRM and the progress being made.

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Dr. Karen Ring explaining embryonic development to kids

We also used Play Doh so that the kids could model cell division and specialization during embryonic development. But mostly it was so the kids could play with the Play Doh while we talked to their parents.

It is shameless I know but when you are competing against more than 130 other booths for people’s attention – and some of these booths had live snakes, virtual reality devices, or they just let kids throw and hit things – you have to be creative.

And creativity was certainly the key word, because Discovery Day – part of the annual week-long Bay Area Science Fair – was filled with booths from companies and academic institutions promoting every imaginable aspect of science.

So why were we there? Well, first, education has been an important part of CIRM’s mission ever since we were created. Second, we’re a state agency that gets public funding so we feel we owe it to the public to explain how their money is being used. And third, it’s just a lot of fun.

NASA was there, talking about exploring deep space. And there were booths focused on exploring the oceans, and saving them from pollution and over-fishing. You could learn about mathematics and engineering by building wacky-looking paper airplanes that flew long distances, or you could just sit in the cockpit of a fighter jet.

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And everywhere you looked were families, with kids running up to the different booths to see what was there. All they needed was a little draw to get them to stick around for a few minutes, so you could talk to them and explain to them what stem cells are and why they are so amazing. Some of the kids were fascinated and wanted to know more: some just wanted to use the Play Doh;  at least one just wanted to eat the Play Doh, but fortunately we were able to stop that happening.

It was an amazing sight to see a baseball stadium filled with tens of thousands of people, all there to learn about science. At a time when we are told that kids don’t care about science, that they don’t like math, this was the perfect response. All you had to do was look around and see that kids were fascinated by science. They were hungry to learn how pouring carbon dioxide on a candle puts out the flame. They delighted in touching an otter pelt and feeling how silky smooth it is, and then looking at the pelt under a microscope to see just how extraordinarily dense the hairs are and how that helps waterproof the otter.

And so yes, we used Play Doh and a white board person to lure the kids to us. But it worked.

There was another booth where they had a couple of the San Francisco 49er’s cheerleaders in full uniform. I don’t actually know what that had to do with teaching science but it was very popular with some of the men. Maybe next year I could try dressing up like that. It would certainly draw a crowd.

Meat the future of stem cells. And I do mean “meat”.

'...And just a pince of stem cells.'

Over the years there have been a lot of interesting, odd ball, even a few really rather crazy stories about stem cell research that have made the news. So in honor of Halloween, we thought we’d look back at a few of them to remind ourselves that not all science is worthy of pursuit.

Celebrity meat:

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Back in 2014 a company called BiteLabs claimed it was going to make  “fine artisanal salami from meat that has been lab-grown from celebrity tissue samples.” You read that right. They were going to make salami from famous people.

Here’s how they described the process. First they would take a small sample of stem cells from the celebrity, the kind of cell that is used to grow and repair damaged muscles. Then they would grow those cells in the lab, increasing their number to millions of muscle cells. Those are then ground up, mixed with regular salami and some spices, fats and oils until you had the desired consistency and texture.

Then they were stuffed into casings, and dried, aged and cured until you end up with celebrity salami.

Not surprisingly it attracted a lot of attention. The Twitterverse was filled with images of celebrities people wanted to “eat” – Jennifer Lawrence, ‘a new kind of Hunger Games’. It was also filled with headlines from magazines like Cosmopolitan asking “Is this the weirdest food of all time”.

Turns out it was more of a joke, or at least a fun way to get people discussing bioethics and pushing the boundaries – or maybe it was the buttons – of tech and society.

Meet the most expensive meat in the world

If that was meant to be a joke then some researchers at Maastricht University in the Netherlands didn’t get it. Because the next year they actually produced a burger that was made out of stem cells.

They took some bovine – aka ‘cow’ – stem cells, grew them in the lab (this took three months so definitely not a “fast food”), then mixed them with salt, breadcrumbs and egg and cooked them in a little butter and sunflower oil.

People who tried it described it as “tough” and “not that juicy”. Harder to stomach than the burger itself was the price tag, more than $300,000.

A mammoth task

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It’s not just meat that is attracting the attention of stem cell researchers. More recently a team of Korean and Russian scientists decided it might be fun to try and use stem cells to “grow” a mammoth. You know, the giant, woolly, elephant-like creatures that went extinct thousands of years ago – except for occasional starring roles in the Ice Age animated movies.

They were going to take some DNA from the remnants of a mammoth found in the frozen tundra in Siberia, decode its genome, then create a functioning cell nucleus and transplant that into an elephant’s embryo. Easy right? What could possible go wrong (for some suggestions see Jurassic Park/World).

Maybe if that doesn’t work out they could just grow the cells into meat and market them. Mammoth burgers. Sounds yummy doesn’t it.

Happy Halloween.

 

Trash talking and creating a stem cell community

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Imilce Rodriguez-Fernandez likes to talk trash. No, really, she does. In her case it’s cellular trash, the kind that builds up in our cells and has to be removed to ensure the cells don’t become sick.

Imilce was one of several stem cell researchers who took part in a couple of public events over the weekend, on either side of San Francisco Bay, that served to span both a geographical and generational divide and create a common sense of community.

The first event was at the Buck Institute for Research on Aging in Marin County, near San Francisco. It was titled “Stem Cell Celebration” and that’s pretty much what it was. It featured some extraordinary young scientists from the Buck talking about the work they are doing in uncovering some of the connections between aging and chronic diseases, and coming up with solutions to stop or even reverse some of those changes.

One of those scientists was Imilce. She explained that just as it is important for people to get rid of their trash so they can have a clean, healthy home, so it is important for our cells to do the same. Cells that fail to get rid of their protein trash become sick, unhealthy and ultimately stop working.

Imilce is exploring the cellular janitorial services our bodies have developed to deal with trash, and trying to find ways to enhance them so they are more effective, particularly as we age and those janitorial services aren’t as efficient as they were in our youth.

Unlocking the secrets of premature aging

Chris Wiley, another postdoctoral researcher at the Buck, showed that some medications that are used to treat HIV may be life-saving on one level, preventing the onset of full-blown AIDS, but that those benefits come with a cost, namely premature aging. Chris said the impact of aging doesn’t just affect one cell or one part of the body, but ripples out affecting other cells and other parts of the body. By studying the impact those medications have on our bodies he’s hoping to find ways to maintain the benefits of those drugs, but get rid of the downside.

Creating a Community

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Across the Bay, the U.C. Berkeley Student Society for Stem Cell Research held it’s 4th annual conference and the theme was “Culturing a Stem Cell Community.”

The list of speakers was a Who’s Who of CIRM-funded scientists from U.C. Davis’ Jan Nolta and Paul Knoepfler, to U.C. Irvine’s Henry Klassen and U.C. Berkeley’s David Schaffer. The talks ranged from progress in fighting blindness, to how advances in stem cell gene editing are cause for celebration, and concern.

What struck me most about both meetings was the age divide. At the Buck those presenting were young scientists, millennials; the audience was considerably older, baby boomers. At UC Berkeley it was the reverse; the presenters were experienced scientists of the baby boom generation, and the audience were keen young students representing the next generation of scientists.

Bridging the divide

But regardless of the age differences there was a shared sense of involvement, a feeling that regardless of which side of the audience we are on we all have something in common, we are all part of the stem cell community.

All communities have a story, something that helps bind them together and gives them a sense of common purpose. For the stem cell community there is not one single story, there are many. But while those stories all start from a different place, they end up with a common theme; inspiration, determination and hope.

 

Celebrating Stem Cell Awareness Day with SUPER CELLS!

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To all you stem cell lovers out there, today is your day! The second Wednesday of October is Stem Cell Awareness Day (SCAD), which brings together organizations and individuals that are working to ensure the general public realizes the benefits of stem cell research.

For patients in desperate need of treatments for diseases without cures, this is also a day to recognize their struggles and the scientific advances in the stem cell field that are bringing us closer to helping these patients.

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Induced pluripotent stem cells.

How are people celebrating SCAD?

This year, a number of institutes in California are hosting events in honor of Stem Cell Awareness Day. Members of the CIRM team will be speaking on Saturday about “The Power of Stem Cells” at the Buck Institute for Research on Aging in Novato (RSVP on Facebook) and at the Berkeley Student Society for Stem Cell Research Conference in Berkeley (RSVP on Eventbrite). There are also a few SCAD events going on this week in Southern California. You can learn more about these all events on our website.

You can also find out about other SCAD celebrations and events on social media by following the hashtag #StemCellAwarenessDay and #StemCellDay on Twitter.

Super Cells: The Power of Stem Cells

Super Cells exhibit at the Lawrence Hall of Science

Super Cells exhibit at the Lawrence Hall of Science

Today, the CIRM Stem Cellar is celebrating SCAD by sharing our recent visit to the Lawrence Hall of Science, which is currently hosting an exhibit called “Super Cells: The Power of Stem Cells”.

This is a REALLY COOL interactive exhibit that explains what stem cells are, what they do, and how we can harness their power to treat disease and injury. CIRM was one of the partners that helped create this exhibit, so we were especially excited to see it in person.

Super Cells has four “high-tech interactive zones and a comprehensive educational guide for school children ages 6-14”. You can read more details about the exhibit in this promotional handout. Based on my visit to the exhibit, I can easily say­­ that Super Cells will be interesting and informative to any age group.

The exhibit was unveiled on September 28th, and the Hall told us that they have already heard positive reviews from their visitors. We had the opportunity to talk further with Susan Gregory, the Deputy Director of the Hall, and Adam Frost, a marketing specialist, about the Super Cells exhibit. We asked them a few questions and will share their interview below followed by a few fun pictures we took of the exhibit.


Q: Why did the Lawrence Hall of Science decide to host the Super Cells exhibit?

The Lawrence Hall of Science has a history of bringing in exciting and engaging traveling exhibitions, and we were looking for something new to excite our visitors in the Fall season. When the opportunity presented itself to host Super Cells, we thought it would be a good fit for our audience. Additionally, the Hall is increasing its programming and exhibits in the fields of biology, chemistry and bioengineering.

Q: What aspects of the Super Cells exhibit do you think are valuable to younger kids?

We strive to make our exhibit experiences hands-on and interactive. The Hall believes that the best way for kids to learn science is for them to be active in their learning. Super Cells offers a variety of elements that speak to our philosophy of learning and make learning science more fun.

Q: How is exhibit similar or unique to other exhibits you’ve hosted previously?

 The Hall hosts and develops exhibits across a broad range of scientific, engineering, technology and mathematical topics. We are always looking for exhibits that address recent scientific advances, and also try to showcase cutting edge research.

Super Cells presents both basic cell biology and information about recent medical and scientific advances, so it fits. Also, as mentioned in our behind the scenes story about the exhibit install, in the past many of our traveling exhibits were very large experiences that tended to take up a lot of space on the museum floor. One thing that is great about Super Cells is that it packs a lot of information into a relatively small space, allowing us to keep a number of experiences and activities that our audience has come to love on the floor, instead of removing them to make room.

Q: Will there be any special events at the Hall featuring this exhibit?

On November 11, the Hall will host a fun day of activities centered around DNA and the exhibit. Younger visitors will make DNA bracelets based on the unique traits in their genome, while older kids will isolate their own DNA using a swab from inside their cheek. We are still finalizing the details of this event, but it will definitely happen.

Q:  Why do you think it’s important for younger students and the general public to learn about stem cells and stem cell research?

As UC Berkeley’s public science center, the Hall is committed to providing a window into cutting edge research and the latest scientific information. We think it’s really important for people and kids to learn about the skills and science behind current research so they can be prepared for a future of incredible scientific challenges and opportunities that we can’t foresee.


Super Cells will be open at the Lawrence Hall of Science until November 27th, so be sure to check it out before then. If you don’t live in California, don’t worry, Super Cells will be traveling around the U.S., Europe and Canada. You can find out where Super Cells is touring next on their website.

We hope you enjoy our photos of the Super Cells exhibit!

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Funding stem cell research targeting a rare and life-threatening disease in children

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Photo courtesy Cystinosis Research Network

If you have never heard of cystinosis you should consider yourself fortunate. It’s a rare condition caused by an inherited genetic mutation. It hits early and it hits hard. Children with cystinosis are usually diagnosed before age 2 and are in end-stage kidney failure by the time they are 9. If that’s not bad enough they also experience damage to their eyes, liver, muscles, pancreas and brain.

The genetic mutation behind the condition results in an amino acid, cystine, accumulating at toxic levels in the body. There’s no cure. There is one approved treatment but it only delays progression of the disease, has some serious side effects of its own, and doesn’t prevent the need for a  kidney transplant.

Researchers at UC San Diego, led by Stephanie Cherqui, think they might have a better approach, one that could offer a single, life-long treatment for the problem. Yesterday the CIRM Board agreed and approved more than $5.2 million for Cherqui and her team to do the pre-clinical testing and work needed to get this potential treatment ready for a clinical trial.

Their goal is to take blood stem cells from people with cystinosis, genetically-modify them and return them to the patient, effectively delivering a healthy, functional gene to the body. The hope is that these genetically-modified blood stem cells will integrate with various body organs and not only replace diseased cells but also rescue them from the disease, making them healthy once again.

In a news release Randy Mills, CIRM’s President and CEO, said orphan diseases like cystinosis may not affect large numbers of people but are no less deserving of research in finding an effective therapy:

“Current treatments are expensive and limited. We want to push beyond and help find a life-long treatment, one that could prevent kidney failure and the need for kidney transplant. In this case, both the need and the science were compelling.”

The beauty of work like this is that, if successful, a one-time treatment could last a lifetime, eliminating or reducing kidney disease and the need for kidney transplantation. But it doesn’t stop there. The lessons learned through research like this might also apply to other inherited multi-organ degenerative disorders.

Asterias’ stem cell clinical trial shows encouraging results for spinal cord injury patients

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Jake Javier; Asterias spinal cord injury clinical trial participant

When researchers are carrying out a clinical trial they have two goals: first, show that it is safe (the old “do no harm” maxim) and second, show it works. One without the other doesn’t do anyone any good in the long run.

A few weeks ago Asterias Biotherapeutics showed that their CIRM-funded stem cell therapy for spinal cord injuries appeared to be safe. Now their data suggests it’s working. And that is a pretty exciting combination.

Asterias announced the news at the annual scientific meeting of the International Spinal Cord Society in Vienna, Austria. These results cover five people who got a transplant of 10 million cells. While the language is muted, the implications are very encouraging:

“While early in the study, with only 4 of the 5 patients in the cohort having reached 90 days after dosing, all patients have shown at least one motor level of improvement so far and the efficacy target of 2 of 5 patients in the cohort achieving two motor levels of improvement on at least one side of their body has already been achieved.”

What does that mean for the people treated? A lot. Remember these are people who qualified for this clinical trial because of an injury that left them pretty much paralyzed from the chest down. Seeing an improvement of two motor levels means they are regaining some use of their arms, hands and fingers, and that means they are regaining the ability to do things like feeding, dressing and bathing themselves. In effect, it is not only improving their quality of life but it is also giving them a chance to lead an independent life.

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Kris Boesen, Asterias clinical trial participant

One of those patients is Kris Boesen who regained the use of his arms and hands after becoming the first patient in this trial to get a transplant of 10 million cells. We blogged about Kris here

Asterias says of the 5 patients who got 10 million cells, 4 are now 90 days out from their transplant. Of those:

  • All four have improved one motor level on at least one side
  • 2 patients have improved two motor levels on one side
  • One has improved two motor levels on both sides

What’s also encouraging is that none of the people treated experienced any serious side effects or adverse events from the transplant or the temporary use of immunosuppressive drugs.

Steve Cartt, CEO of Asterias, was understandably happy with the news and that it allows them to move to the next phase:

“We are quite encouraged by this first look at efficacy results and look forward to reporting six-month efficacy data as planned in January 2017.  We have also just recently been cleared to begin enrolling a new cohort and administering to these new patients a much higher dose of 20 million cells.  We look forward to begin evaluating efficacy results in this higher-dose cohort in the coming months as well.”

People with spinal cord injuries can regain some function spontaneously so no one is yet leaping to the conclusion that all the progress in this trial is due to the stem cells. But to see all of the patients in the 10 million stem cell group do well is at the very least a positive sign. Now the hope is that these folks will continue to do well, and that the next group of people who get a 20 million cell transplant will also see improvements.

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Roman Reed, spinal cord injury patient advocate

While the team at Asterias were being cautiously optimistic, Roman Reed, whose foundation helped fund the early research that led to this clinical trial, was much less subdued in his response. He was positively giddy:

“If one patient only improves out of the five, it can be an outlier, but with everyone improving out of the five this is legit, this is real. Cures are happening!”

 

Salk scientists explain why brain cells are genetically diverse

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I’ve always wondered why some sets of genetically identical twins become not so identical later in life. Sometimes they differ in appearance. Other times, one twin is healthy while the other is plagued with a serious disease. These differences can be explained by exposure to different environmental factors over time, but there could also be a genetic explanation involving our brains.

The brain is composed of approximately 100 billion cells called neurons, each with a DNA blueprint that contains instructions that determine the function of these neurons in the brain. Originally it was thought that all cells, including neurons, have the same DNA. But more recently, scientists discovered that the brain is genetically diverse and that neurons within the same brain can have slightly different DNA blueprints, which could give them slightly different functions.

Jumping genes and genetic diversity

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Fred “Rusty” Gage: Photo courtesy Salk Institute

Why and how neurons have differences in their DNA are questions that Salk Institute professor Fred Gage has pursued for more than a decade. In 2005, his lab discovered a mechanism during neural development that causes differences in the DNA of neurons. As a brain stem cell develops into a neuron, long interspersed nuclear elements (L1s), which are small pieces of DNA, copy and paste themselves, seemingly at random, throughout a neuron’s genome.

These elements were originally dubbed “jumping genes” because of their ability to hop around and insert themselves into DNA. It turns out that L1s do more than copy and paste themselves to create changes in DNA, they also can delete chunks of DNA. In a CIRM-funded study published this week in the journal Nature Neuroscience, Gage and colleagues at the Salk Institute reported new insights into L1 activity and how it creates genetic diversity in the brain.

Copy, paste, delete

Gage and his team had clues that L1s can cause DNA deletions in neurons back in 2013. They used a technique called single-cell sequencing to record the sequence of individual neuronal genomes and saw that some of their genomes had large sections of DNA added or missing.

They thought that L1s could be the reason for these insertions and deletions, but didn’t have proof until their current study, which used an improved method to identify areas of the neuronal genome modified by L1s. This method, combined with a computer algorithm that can easily tell the difference between various types of L1 modifications, revealed that areas of the genome with L1s were susceptible to DNA cutting caused by enzymes that home in on the L1 sequences. These breaks in the DNA then cause the observed deletions.

Gage explained their findings in a news release:

“In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person. This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism.”

Jennifer Erwin, first author on the study, further elaborated:

“The surprising part was that we thought all L1s could do was insert into new places. But the fact that they’re causing deletions means that they’re affecting the genome in a more significant way,” says Erwin, a staff scientist in Gage’s group.”

Insights into brain disorders

It’s now known that L1s are important for the brain’s genetic diversity, but Gage also believes that L1s could play a role in causing brain disorders like schizophrenia and autism where there is heightened L1 activity in the neurons of these patients. In future work, Gage and his team will study how L1s can cause changes in genes associated with schizophrenia and autism and how these changes can effect brain function and cause disease.